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    • We demonstrated clearly that the overexpression of sFlt sign

    2024-04-23

    We demonstrated clearly that the overexpression of sFlt-1 significantly increased arginase BQ-788 sodium salt synthesis and enhanced arginase activity in HUVECs (Fig. 3). NO formation is related inversely to serum levels of sFlt-1 in preeclampsia [11]. The disorder of NO formation, which was involved in hypertension and proteinuria in preeclampsia, was induced by impaired NOS activity. The endothelial dysfunction could result from sFlt-1-induced antagonism of VEGF [2]. However, our results suggested that overexpression of sFlt-1 directly led to higher arginase expression and activity in HUVECs. A previous report stated that when either arginase or NOS is activated, it competitively inhibits the action of the other, both by direct utilization of increased amounts of l-arginine and by secondary means [20] [21]. Thus far, our data suggested that higher arginase expression and activity induced by overexpression of sFlt-1 impaired NOS activity, which leads to NO formation disorder. Our data indicated that increased sFlt-1 could not regulate arginase, resulting in abnormal NO synthase associated with a preeclamptic phenotype. Together with previous reports, our results explain the mechanism between sFlt-1, arginase, and NO. Finally, we examined the effect on sFlt-1 by inhibiting arginase. Our data showed that BEC, an arginase inhibitor, impaired sFlt-1 expression in HUVECs (Fig. 2D). This result strongly supported the mechanism that sFlt-1 itself was likely to maintain angiogenic/anti-angiogenic homeostasis against increasing sFlt-1 in preeclampsia. Furthermore, our results indicated that arginase inhibitor could be one of the future treatments targeting sFlt-1 for preeclampsia. This study is the first to report on the relationship between sFlt-1 and arginase. Arginase competes with NOS for the common catalyzing substrate and shifts the metabolism of arginine and urea. Therefore, inhibition of arginase may block the conversion of l-arginine to urea and increase NO synthesis. This result suggested that inhibition of arginase expression and activity on sFlt-1 administration leads to an increase in NOS activity and NO production. NO was reported to decrease sFlt-1 production significantly in hypoxic primary human trophoblast [22]. Therefore, we considered that sFlt-1 negatively regulated itself through inhibition of arginase in HUVECs. One of limitations of our study is the small number of samples. BQ-788 sodium salt synthesis Therefore further research need to be followed in large scale. In conclusion, our findings suggested that a mechanism to maintain a homeostatic state exists; sFlt-1 negatively regulates itself through arginase in pregnancy and a decline in arginase levels leads to preeclampsia. Suppression of arginase owing to an increasing sFlt-1 reduces sFlt-1 itself (see Fig. 4). Moreover, these alterations suggest that arginase inhibitors could be a potential target for the prophylactic treatment of preeclampsia.
    Conflicts of interest
    Acknowledgments We would like to thank Editage (www.editage.jp) for English language editing.
    Introduction L-arginase (E.C 3.5.3.1, L-arginine amidinohydrolase, ARG), one of the urea-cycle enzymes, is a binuclear manganese cluster metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea [1], [2]. Arginase has roots in early life forms and is widely distributed in the five kingdoms of organisms as diverse as bacteria, yeasts, plants, invertebrates and vertebrates [3]. Arginases have been purified and characterized from a wide variety organisms [4]. Also, the crystal structure of arginases from many species has been solved, including those from Homo sapiens[5], Rattus norvegicus[6] and Bacillus caldovelox[7]. Mammalian arginase is active as a trimer, but some bacterial arginases are hexameric [8]. The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn2+ ions coordinate with water, orienting and stabilizing the molecule by allowing water to act as a nucleophile and attack L-arginine, hydrolyzing it into ornithine and urea [9]. In most mammals, two isozymes of this enzyme exist: cytoplasmic urea cycle arginase I (ARG I) or liver arginase which is highly expressed in the liver primarily to carry out ureagenesis via ammonia detoxification [10], [11] and a second mitochondrial isoenzyme arginase II (ARG II) or nonhepatic arginase which is expressed in trace amounts in extra-hepatic tissues that lack a complete urea cycle, especially kidney, prostate gland, brain and lactating mammary gland [12] which is involved in L-arginine homeostasis [13] and regulating L-ornithine pools for subsequent biosynthetic transformations including the biosynthesis of polyamines, glutamate, proline [14] and controlling tissue level arginine for nitric oxide (NO) biosynthesis [15] by competing with inducible nitric oxide synthase (iNOS) for their common substrate, L-arginine, which is an important determinant of the inflammatory response in various organs and regulating nitric oxide-dependent apoptosis [14], [16], [17].